Bone formation is an essential process in embryonic development and plays a critical role in many diseases and conditions which affect millions of humans. For example, osteoporosis is a debilitating disease characterized by excessive bone loss that affects approximately 14 million Americans and costs the U.S. health care system nearly $10 billion annually. In about 40 percent of women and 13 percent of men over 50, osteoporosis is the underlying cause of most hip, spine, and wrist fractures. Recent studies estimate that as much as 70 percent of the variation in bone density is inherited. Bone density reaches adult levels at approximately 18–22 years of life and remains relatively stable until middle age. Loss of bone density in the elderly is the consequence of known factors such as menopause, inadequate nutrition, specific medical conditions, and unknown factors such as a person's genetic constitution. Physicians have very few available drugs to treat declining bone density and need drugs that will promote bone formation in patients.
Bone is continuously remodeled through a coupled process of bone resorption and bone formation. During bone resorption, osteoclasts attach to the mineralized bone matrix and excavate small pits on the bone surface, releasing bone collagen and minerals in the circulation. Subsequently, cross-linked N-telopeptides are released into the bloodstream during osteoclastic activity. During bone formation, osteoblasts are recruited to the newly resorbed areas on the bone where they deposit new collagen. When resorption and formation are in balance, there is no net change in bone mass. After a resting phase during which the bone is mineralized, the remodeling cycle begins again.
In addition to bone formation, another important role for osteoprogenitor cells is in vascular calcification (see, e.g. Curr Opin Nephrol Hypertens (2000) 9: 11–15). Calcification is a component of vascular disease that usually occurs in concert with atheroma formation but through distinct pathophysiological processes. Vessel wall osteoprogenitor cells known as calcifying vascular cells can form bone matrix proteins and calcified nodules, analogous to osteoblastic differentiation in bone. These cells have been isolated from the tunica media of bovine and human arteries, and both in-vitro tissue culture models and mouse models of vascular calcification have been established. Studies of the effects of diabetes mellitus, hyperlipidemia, estrogens and glucocorticoids on calcifying vascular cell function provide insight into the relationship between common human disease states and vascular calcification.
While endochondral bone formation has been fairly well characterized from a morphological perspective, this process remains largely undefined at a gene transcriptional level. In vitro and in vivo studies have suggested that bone morphogenetic protein-2 (BMP-2) plays an important role in bone formation, however a detailed understanding of the molecular mechanisms involved would be useful to identify potential genetic targets for controlling bone formation. Accordingly, an understanding of the biochemical and molecular events underlying bone formation, and in particular the identity of the gene(s) expressed during bone and cartilage formation, would provide significant diagnostic and therapeutic applications for the treatment of diseases relating to bone and cartilage formation or resorption, such as osteoporosis, bone fractures and rheumatoid arthritis.